Process for producing anhydrous granulation of a medicinally active waterlabile powder



PROCESS FOR PRODUCING ANHYDROUS GRAN- ULATION OF A IVTEDICINALLY ACTIVE WATER- LABILE POWDER Alfred Charles de Grunigen, Nanuet, N.Y., assignor to American Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Filed Sept. 12, 1958, Ser. No. 760,572

Claims. (Cl. 167-82) taining medicinals, vitamins or nutrients, it has been customary to granulate the dry powder constituting or containing the active ingredient by mixing it with an aqueous solution of a gum, such as gum acacia in water, to form a thick paste which is forced through a coarse screen and permitted to dry, thereby forming granules. These granules are then passed through a finer screen to break them up, mixed with a lubricant such as stearic acid powder or magnesium stearate and/or a talc, and blended thoroughly. The granules are then compressed in a standard tablet compressing machine in which the granules are permitted to flow into a die and a punch brought down to compress the material, thereby forming a tablet, and the completed tablet is then ejected from the machine.

Granulation is necessary because many dry powders will not cohere. Also, if the powder is run through the machine, it bridges or flows unevenly so as to give nonuniform size to the tablets, or forms fragile tablets so that the tablets easily disintegrate into the original powder in release from the forming dies. 1

In the past, it has been found that certain rnedicinals, vitamins, nutrients, etc. in the form of powders are sensitive to the moisture used in the granulating solutions so that, accordingly, the powder loses its potency or discolors or is otherwise damaged. Similarly, it has been observed in the past that certain binding agents suffer from the same deficiencies.

According tothe present invention, water sensitive powders which either deteriorate in the presence of moisture or otherwise react undesirably, such as efiervescent compositions, are granulated by means of a solution of water permeable ethyl cellulose. The granules are useable in standard tableting machines without substantial change in operating conditions and produce satisfactory tablets.

It is necessary that the solvent for the water permeable ethyl cellulose be substantially nonaqueous. It is also essential that the solvent be volatile and substantially nonreactive with the components to produce disintegration, discoloration or other undesirable reactions and it should not be sufliciently toxic so that minute quantities which remain after evaporation of the solvent would constitute a a toxicity hazard.

The solvents found suitable are lower alkanols, such as methanol, ethanol, isopropanol and the like. The alcohols may be completely anhydrous or they may contain is quite unsuitable.

znsesss Patented Apr. 18, 1961.

a small amount of moisture. For example, commercial ethanol or slightly moist (99%) isopropanol may be used. The small amount of water is so tightly held in these alcohols that it does not react with tablet materials.

The solvent should be one which is volatile under conditions under which the powder to be tableted is stable and which is inert towards the powder, and in which the binding gum is soluble. The amount of solvent to be used is such that a paste results in the granulating operation with the individual granules sufficiently firm to maintain their shape and yet sufiiciently soft to be forced through the granulating screen. The quantity of binder dissolved in the solvent is such as to result'in tablets of a desired solidity. More of the binder results in a firmer tablet. Finer powders usually require more binder and solvent than coarse powders. Mixtures of powders may be granulated together or granulated separately and then mixed. The amount of solvent is usually between about 10 and 40 milliliters per 100 grams of powder, and usually this amount of solvent should contain from 1 to 10 grams of the binding agent, such as Water permeable ethyl cellulose.

Ethyl cellulose, which is water permeable and has an ethoxyl content of from about 43% to 50%, appears to be uniquely suited. This is not generally true of hydrophilic cellulose ethers. For example, methyl cellulose Tablets produced by granulating compositions containing ascorbic acid with aqueous solutions of methyl cellulose discolor rapidly on exposure to air and are unacceptable. Similar'difiiculties are encountered with other moisture-sensitive materials.

It is not feasible to use ethyl cellulose of too low water permeability. Thus, if water insoluble ethyl cellulose is used, granulation occurs but the tablets are not practically useful as they do not disintegrate in the gastrointestinal tract at a sufiicient rate to be practical. It is therefore essential that the ethyl cellulose be water permeable although it is not water soluble. In general, the best ethyl celluloses to be used in the present invention are, as stated above, those having an eth'oxyl content of between 43% to 50%. This isnot the absolute limit of usefulness as other ethyl celluloses which are still water permeable but not water soluble can be used. In order to avoid awkward language throughout the remainder of the specification and in the claims, the term water permeable will be limited to products which can be permeated by water but are not soluble in it. A typical example of a commercial water permeable ethyl cellulose is one having an ethoxyl content of 47% which softens at C. and is soluble in ethyl acetate, ethylene dichloride, benzene, toluene, xylene, butyl acetate, acetone and carbon tetrachloride in addition to the lower alkanols.

While the amount of the water permeable ethyl cellulose is not sharply critical, for practical utility the amounts should be between 0.5% and 10% by weight of the solids in the'tablet. No single amount of ethyl cellulose will give optimum results with every medicament as the best amounts will vary somewhat with the solubility of the medicament in water. Optimum amounts, however, will always fall within the range given above.

Several methods can be used in formulating the composition of this invention. The method which eifects the desired results with the greatest facility involves mixing the active ingredient in the form of a powder with the ethyl cellulose binder, and fillers where necessary, all in the dry state. It is sometimes necessary to screen some or all of the dry ingredients prior to mixing. This mixing step is followed by the addition of the solvent, preferably in small quantities, accompanied by mixing to form a homogeneous paste. On the other 3 hand, the binding agent may first be dissolved in the solvent; the solution may be assisted by heating the solution. The solution is then added to the powder which is to be tableted; a homogeneous paste is thus formed.

The paste formed by either of the above procedures is then passed through a screen to break it up into granules and the granules are allowed to dry at either room temperature or elevated temperatures. The drying may be expedited by heating in a drying oven (about 35 C. to 50 C.) due caution being used to insure that the fumes do not cause fire hazards or safety hazards to the health of the operator. When drying is effected at room temperature (about 24 C. a drying time of 12 to 20 hours should be used. When elevated drying temperatures are used, the drying time will be about fourto eight hours. After drying, the granules may be passed through a screen to break them up into smaller granules and separate granules which have become adherent to each other, thereby forming a free-flowing granulation suitable for tablet manufacture in automatic machines. 7

Usually the granules are then lubricated with a lubricant which may be a water-insoluble soap such as magnesium stearate, calcium stearate, zinc stearate orother lubricants such as sodium stearate, stearic acid, talc, mineral oil, boric acid, sodium lauryl sulfate or calcium ricinoleate. The lubricant and the dry granules are mixed until homogeneous, and the composition is then ready to be compressed in .a tablet compressing machine in accordance with the standard procedures. The tablets are firm, solid, completely satisfactory tablets which do not break under normal shipping conditions. The combination of an ethyl cellulose binder and a lower alcohol is particularly advantageous because the granules are easily tableted with a minimum of pressure. The solvent is accepted without question in all pharmacological operations and the binder is stable, .does not .discolor sensitive materials, is completely free from odors and acceptable internally.

My new process is particularly useful with compounds such as ascorbic acid which, when tableted by conventional'procedures, would turn brown and discolor after only a short storage period. When granulated in accordance with the present process, :the ascorbic acid tablets will remain pure white indefinitely.

A mixture of sodium bicarbonate and tartaric acid may be granulated by my process to form tablets. The efiervescent action on the addition of water to this mixture is well known. Other -materials with which it is particularly advantageous to use an ethyl cellulose binder include such materials as antibiotics such as chlortetracycline, bacitracin, oxytetracycline, penicillin or mixtures of these, vitamin products such as ascorbic acid and thiamine, hygroscopic mixtures such as those containing citric acid or calcium cyanamide and many other pharmaceutical products such as 2-methyl-2-n propyl propanediol-1,3-dicarbamate(meprobamate).

Additionally, many compounds which have been previously tableted using gum acacia in water as a granulating agent may be granulated using ethyl cellulose as a binder and they will .be found to be either more storagestable or compatible in mixtures with materials which are water soluble. For purposes of convenience,-ethyl cellulose may be used with all powders, even those which may be satisfactorily granulated with water in order to give a line of tablets which are completely-uniform and consistent in all of their storage and solubility'characteristics.

The following examples are illustrative of certain spe- 4 EXAMPLE 1 Ascorbic acid tablets, 500 mg./ tablet Percent Ascorbic acid 79.2 Lactose 11.3 Ethocel 5.0 Corn starch powder 2.0 Alginic acid 1.5 Magnesium stearate 1.0

99% isopropanoll8% by volume of total weight of solids.

The ascorbic acid, lactose and ethocel are mixed together with agitation. The isopropanol is sprinkled in while mixing, producing granules. After drying at 42 C. for six hours, the granules are screened through a No. 2 B Fitz screen. The remaining ingredients areadded to the granules and the whole is mixed well. The material is then compressed into tablets.

EXAMPLE 2 Procaine penicillin, 250,000 LL/mblet Percent Procaine penicillin 49.0 Ethocel 1.0 White blank granulation for penicillin tablets 47.3 Alginic acid 2.0 Magnesium stearate 0.7

99% isopropanol'18%' by volume of total weight of solids.

1 CaCOs71-%, vCaHzlEOi1'4 corn sbaroh13%, acacia powder2%.

The penicillin and ethocel are mixed together and the isopropanol sprinkled in while mixing producing granules. After drying at room temperature (24 C.), these granules are screened as in Example 1. The granules plus the remaining ingredients are'blended, in the order mentioned, and mixed well. The material is then compressed into tablets.

I claim:

1. In the process of granulating powders for tablet manufacture, the improvement which comprises the step of effecting granulation of the powder with a solution of from 0.5% to 10% of water permeable ethyl cellulose in a substantially water free lower alkanol solvent.

2. ,A process according toclaim 1 in which the lower alkanol is ethanol.

'3. A processaccording to claim lin which the lower alkanol is isopropanol.

4. A process according to claim 3 in which the powder contains ascorbic acid as a medicament.

5. A process according to claim 3 in which the powder comprises procaine penicillin.

6. In the process of granulating powders-for tablet manufacture, the improvement which comprises mixing said powders in the dry state with from 0.5% to 10% by weight of. water permeable ethyl cellulose and then adding a sufiicient quantityof substantially water free lower alkanol to form a homogeneous paste.

7. A process according to claim 6 in which the lower ethanol is ethanol.

.8. A proc ss accordirl;g to laim 6 in whi h t e l we alkanol is isopropanol.

:9 A process according to claim 8 in which the powder contains ascorbic acid as a medicament.

10. A process accq idin to claim 8 in which the po der comprises procain penicillin.

(References .on following page) References Cited in the file of this patent UNITED STATES PATENTS Andersen Nov. 5, 1946 FOREIGN PATENTS Australia Ian. 11, 1940 6 OTHER REFERENCES Pharm. Journal, February 20, 1943, p. 67.

Little: Tablet Making, Northern Pub. Co., England, 1949, pp. 34, 86 and 87.

Silver: Manufacture of Compressed Tablets, F. U. Stokes Machine Co., Phila., 1944, pp. 6 and 7. 

1. IN THE PROCESS OF GRANULATING POWDERS FOR TABLET MANUFACTURE, THE IMPROVEMENT WHICH COMPRISES THE STEP OF EFFECTING GRANULATION OF THE POWDER WITH A SOLUTION OF FROM 0.5% TO 10% OF WATER PERMEABLE ETHYL CELLULOSE IN A SUBSTANTIALLY WATER FREE LOWER ALKANOL SOLVENT. 